Copper chelator ATN-224 inhibits endothelial function by multiple mechanisms

Copper is required for the proliferation of endothelial cells and copper-lowering therapy reduces tumour growth in animal models. It has been reported that ATN-224, a novel copper chelator, potently inhibits the activity of the copper-dependent enzyme superoxide dismutase 1 (SOD1) in endothelial cel...

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Published in:Microvascular research Vol. 77; no. 3; pp. 314 - 326
Main Authors: Lowndes, Sarah A., Sheldon, Helen V., Cai, Shijie, Taylor, Jennifer M., Harris, Adrian L.
Format: Journal Article
Language:English
Published: United States Elsevier Inc 01.05.2009
Subjects:
Angiogenesis
AQP1
ATN-224
Chelating Agents - pharmacology
Chelation Therapy
Copper chelation
Down-Regulation
Endothelium, Vascular - drug effects
Endothelium, Vascular - metabolism
Enzyme Inhibitors - pharmacology
Gene Silencing
Heme Oxygenase-1 - genetics
Heme Oxygenase-1 - metabolism
HO-1
Humans
Microarray Analysis
Molybdenum - pharmacology
Neovascularization, Physiologic - genetics
Pericytes - drug effects
Pericytes - pathology
RNA Interference
RNA, Messenger - metabolism
RNA, Small Interfering - genetics
RNA, Small Interfering - metabolism
SOD1
Superoxide Dismutase - genetics
Superoxide Dismutase - metabolism
Transfection
Up-Regulation
SDF-1
CXCR4
HO-1
FACS
NRF1
ATN-224
RHAMM
AQP1
Angiogenesis
BT
HUVEC
qPCR
PBS
PEG-SOD
RNAi
ANGP2
FGF
Copper chelation
GPX3
IL-1
PGES2
TXNRD1
VEGF
GSR
siRNA
SOD2
KLF2
SOD1
FCS
TM
ITB4
ISSN:0026-2862, 1095-9319, 1095-9319
Online Access:Get full text
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Summary:Copper is required for the proliferation of endothelial cells and copper-lowering therapy reduces tumour growth in animal models. It has been reported that ATN-224, a novel copper chelator, potently inhibits the activity of the copper-dependent enzyme superoxide dismutase 1 (SOD1) in endothelial cells. We performed microarray analysis of gene expression in endothelial cells exposed to ATN-224 which revealed upregulation of stress response genes including heme-oxygenase 1 (HO-1) and differential regulation of several genes previously implicated in angiogenesis including CXCR4, ANGP2, PGES2, RHAMM, ITB4 and AQP1 ( p < 0.01). These changes were confirmed on qPCR. Treatment of HUVEC with ATN-224 caused increased superoxide levels, phospho-ERK signalling, nuclear NRF1 expression, HO-1 expression and induction of the anti-apoptotic proteins P21, BCL2 and BCLXL. There was also nuclear translocation of SOD1. SOD1 RNA interference replicated the effects of ATN-224 on endothelial cell function but did not cause upregulation of HO-1 or PGES2, suggesting additional mechanisms of action of ATN-224. Downregulation of AQP1, which has been shown to have a role in angiogenesis, was seen with both ATN-224 and SOD1 siRNA. AQP1 expression could be rescued after ATN-224 by added copper. RNA interference to AQP1 inhibited endothelial proliferation and migration, confirming the role of AQP1 in endothelial cell function. Therefore regulation of AQP1 may represent an important action of copper chelation therapy.
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ISSN:0026-2862
1095-9319
1095-9319
DOI:10.1016/j.mvr.2009.01.003